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Abstract:

In one embodiment a layered pharmaceutical formulation includes two or
more pharmaceutical layers and an intermediate layer disposed between at
least two of the two or more pharmaceutical layers, the intermediate
layer configured to dissolve in vivo to thereby leave the two or more
pharmaceutical layers substantially intact. In one embodiment, an active
pharmaceutical ingredient in at least one of the pharmaceutical layers is
selected from bupropion, zonisamide, naltrexone, topiramate, phentermine,
metformin, olanzapine and fluoxetine.

Claims:

1-6. (canceled)

7. A method for affecting weight loss in a patient, comprising:
identifying a patient in need of weight loss; administering to the
patient a layered pharmaceutical formulation comprising a first
pharmaceutical layer comprising naltrexone, a second pharmaceutical layer
comprising bupropion, and an intermediate layer disposed between the
first and the second pharmaceutical layers, wherein the intermediate
layer is configured to rapidly dissolve in vivo, and thereby leave the
first and the second pharmaceutical layers substantially intact but
physically separated, and wherein the dissolution profile of naltrexone
in the pharmaceutical formulation is substantially the same as a single
compressed tablet of naltrexone having the same size and shape as the
first pharmaceutical layer, and wherein the dissolution profile of
bupropion in the layered pharmaceutical formulation is substantially the
same as a single compressed tablet of the same pharmaceutical
composition, size and shape as the second pharmaceutical layer.

8. The method of claim 7, wherein the intermediate layer comprises a
monosaccharide, a disaccharide or a starch.

12. The method of claim 7, wherein the first pharmaceutical layer
comprises between about 2 mg and about 35 mg of sustained-release
naltrexone.

13. The method of claim 7, wherein the first pharmaceutical layer
comprises between about 4 mg and about 10 mg of the sustained-release
naltrexone.

14. The method of claim 7, wherein the second pharmaceutical layer
comprises between about 50 mg and about 200 mg of sustained-release
bupropion.

15. The method of claim 7, wherein the second pharmaceutical layer
comprises between about 75 mg and about 150 mg of the sustained-release
bupropion.

16. The method of claim 7, wherein the second pharmaceutical layer
comprises between about 85 mg and about 100 mg of the sustained-release
bupropion.

17. The method of claim 7, wherein the first and the second
pharmaceutical layers separate in vivo in less than 1 minute.

18. A method for affecting weight loss in a patient, comprising:
identifying a patient in need of weight loss; administering to the
patient a layered pharmaceutical formulation comprising a first
pharmaceutical layer comprising zonisamide, a second pharmaceutical layer
comprising bupropion, and an intermediate layer disposed between the
first and the second pharmaceutical layers, wherein the intermediate
layer is configured to rapidly dissolve in vivo, and thereby leave the
first and the second pharmaceutical layers substantially intact but
physically separated, and wherein the dissolution profile of zonisamide
in the pharmaceutical formulation is substantially the same as a single
compressed tablet of zonisamide having the same size and shape as the
first pharmaceutical layer, and wherein the dissolution profile of
bupropion in the layered pharmaceutical formulation is substantially the
same as a single compressed tablet of the same pharmaceutical
composition, size and shape as the second pharmaceutical layer.

19. The method of claim 18, wherein the intermediate layer comprises a
monosaccharide, a disaccharide or a starch.

23. The method of claim 18, wherein the second pharmaceutical layer
comprises between about 50 mg and about 200 mg of sustained-release
bupropion.

24. The method of claim 18, wherein the second pharmaceutical layer
comprises between about 75 mg and about 150 mg of the sustained-release
bupropion.

25. The method of claim 18, wherein the second pharmaceutical layer
comprises between about 85 mg and about 100 mg of the sustained-release
bupropion.

26. The method of claim 18, wherein the first and the second
pharmaceutical layers separate in vivo in less than 1 minute.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. patent application Ser.
No. 11/937,421, filed Nov. 8, 2007, now U.S. Pat. No. 8,088,786, issued
on January 3, 2012, which claims priority under 35 U.S.C. §119 to
U.S. Provisional Application No. 60/865,157, filed Nov. 9, 2006, each of
which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to pharmaceutical formulations having two or
more pharmaceutical layers interspersed with one or more intermediate
layers, wherein the pharmaceutical layers include, but are not limited
to, pharmaceutical compositions useful for affecting weight loss,
suppressing appetite and/or treating obesity-related conditions in
individuals.

[0004] 2. Description of the Related Art

[0005] Certain types of layered tablets are known in pharmaceutical
applications. Some pharmaceutical applications separate potentially
interacting layers from one another within a tablet. For example, U.S.
Pat. No. 6,576,256 discloses separating potentially interacting compounds
from each other using separate flat layers of a tablet, concentric
layers, coated beads or granules, and/or using buffers. Thombre, A. G.,
L. E. Appel, et al. (2004), "Osmotic drug delivery using swellable-core
technology" J. Control Release 94(1): 75-89 discloses a core tablet
containing a drug and a water-swellable component, and one or more
delivery ports in different core configurations including a
tablet-in-tablet (TNT) bilayer and trilayer formation. U.S. Pat. No.
6,706,283 discloses an osmotic delivery device fabricated in a bilayer
geometry, wherein the core comprises a sweller layer "sandwiched" between
two drug layers. The coating of a bilayer tablet may include a water
permeable membrane, but is substantially impermeable to the drug and/or
the excipients contained therein. U.S. Pat. No. 6,630,165 discloses
dosage forms and methods for providing sustained release reboxetine
including a trilayered compressed core with a first component drug layer,
a second component push layer and a third component barrier layer
separating the drug layer from the push layer. The barrier layer is inert
with the respect to the composition of the drug layer and substantially
impermeable, such that the drug and the components of the push layer are
prevented from mixing.

[0006] Among multiple layer tablet forms, one type includes a first layer
to provide immediate release of a drug and a second layer to provide
controlled-release of the drug. U.S. Pat. No. 6,514,531 discloses coated
trilayer immediate/prolonged release tablets comprising zolpidem
hemitartrate. U.S. Pat. No. 6,087,386 discloses a trilayer tablet with an
enalapril layer, a losartan potassium layer and a second enalapril
maleate layer or an excipient layer. U.S. Pat. No. 5,213,807 discloses an
oral trilayer tablet with a core comprising a nonsteroidal
anti-inflammatory drug (NSAID), ibuprofen and ibuprofen salts and an
intermediate coating comprising a substantially impervious/impermeable
material to the passage of ibuprofen. U.S. Pat. No. 6,926,907 discloses a
trilayer tablet that separates famotidine contained in a film coat from a
core comprising controlled-release naproxen formulated using excipients
which control the drug release. The film coat is an enteric coating
configured to delay the release of naproxen until the dosage form reaches
an environment where the pH is above four.

SUMMARY

[0007] An embodiment provides a layered pharmaceutical formulation
comprising two or more pharmaceutical layers and an intermediate layer
disposed between at least two of the two or more pharmaceutical layers.
In some embodiments the intermediate layer is configured to dissolve in
vivo to thereby leave the two or more pharmaceutical layers substantially
intact, but physically separated, essentially forming two distinct pills.
In some embodiments the dissolution rate of one of the separated two or
more pharmaceutical layers is substantially similar to that of a singly
compressed tablet comprising the same pharmaceutical composition as that
of the pharmaceutical layer.

[0008] Use of a first compound and a second compound in the preparation of
a medicament for affecting weight loss, suppressing appetite and/or
treating an obesity-related condition, wherein the medicament comprises
layered pharmaceutical formulations of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Other aspects of the disclosure will be readily apparent from the
description below and the appended drawings, in which like reference
numerals refer to similar parts throughout, which are meant to illustrate
and not to limit the disclosure, and in which:

[0019] Embodiments of the present disclosure provide significant
improvements to multilayer tablet technology. In an embodiment, a layered
pharmaceutical formulation comprises two or more pharmaceutical layers
and at least one intermediate layer disposed between at least two of the
two or more pharmaceutical layers. The at least one intermediate layer is
configured to dissolve in vivo to thereby leave the two or more
pharmaceutical layers substantially intact. In some embodiments the
dissolution rate of one or more of a separated pharmaceutical layer is
substantially similar to that of a singly compressed tablet comprising
the same pharmaceutical composition as that of the pharmaceutical layer.
The separated pharmaceutical layer thus has an independent and
predictable dissolution profile.

[0020] A dissolution profile for a drug comprises the known dissolution
rate and particular dissolution characteristics of the drug. A
predictable dissolution profile for a specific drug allows for more
accurate treatment of a given symptom. Predictable dissolution profiles
for different drugs within a multilayer tablet allow for coordinated
treatment of multiple symptoms with a single pharmaceutical formulation.

[0021] In general, multilayer pharmaceutical formulations present
challenges in maintaining predictable dissolution profiles. For example,
in vivo conditions often disrupt an otherwise predictable multilayer
pharmaceutical formulation dissolution profile. A multilayer tablet may
be manufactured with drugs of known dissolution profiles. Once the
multilayer tablet is ingested by a patient, however, there is no
guarantee that each drug will dissolve as predicted by its individual
dissolution profile. Drug configuration within a tablet, tablet shape,
excipients or fillers in the tablet, tablet coatings and in vivo
conditions may all affect the dissolution profiles. Additionally,
interaction between different drugs within a multilayer tablet may cause
a change in dissolution profile for one or more compositions within the
multilayer tablet.

[0022] Further, in one possible in vivo condition, if the multilayer
tablet becomes attached to the lining of the stomach, only a portion of
the tablet would be exposed to the stomach fluids. The dissolution of the
exposed portion of the tablet may occur at a more predictable rate while
the unexposed portion of the multilayer tablet shielded from the stomach
fluids would have a longer dissolution profile than would otherwise be
expected from a singly compressed tablet of an identical composition. As
mentioned above, having a multilayer tablet is desirable for ease of
administration of multiple pharmaceutical compositions within a single
tablet. Thus, it is desirable to configure a multilayer pharmaceutical
formulation such that each pharmaceutical layer has a predictable
dissolution profile.

[0023] Herein disclosed is a pharmaceutical formulation comprising two or
more pharmaceutical layers and at least one intermediate layer configured
to dissolve in vivo to thereby leave the two or more pharmaceutical
layers substantially intact. In preferred embodiments the dissolution
rate of one or more of the separated pharmaceutical layers is
substantially similar to that of a singly compressed tablet comprising
the same pharmaceutical composition as that of the pharmaceutical layer.
In some embodiments, the pharmaceutical layer comprises a single
pharmaceutically active compound or drug. In other embodiments the
pharmaceutical layer comprises a pharmaceutical composition. The term
"pharmaceutical composition" refers to a mixture of a chemical compound
or compounds (e.g., a drug or drugs) with additional pharmaceutical
components, such as diluents or carriers. Herein, the term "drug" is
synonymous with the term "pharmaceutically active ingredient." The
pharmaceutical composition facilitates administration of the drug to an
organism. Pharmaceutical compositions can also be obtained in the form of
pharmaceutically acceptable salts by reacting drug compounds with
inorganic or organic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0024] In some embodiments the two or more pharmaceutical layers comprise
one or more immediate-release formulations. The term "immediate-release"
is used herein to specify that the immediate release formulation is not
configured to alter the dissolution profile of the pharmaceutical layer.
For example, an immediate release pharmaceutical layer may be a
pharmaceutical composition that does not contain ingredients included for
the purpose of altering the dissolution profile. In some embodiments the
two or more pharmaceutical layers comprise one or more controlled-release
formulations. The term "controlled-release" is used herein in its
ordinary sense and thus includes pharmaceutical compositions combined
with ingredients to alter their dissolution profile. A
"sustained-release" formulation is a type of controlled-release
formulation, wherein ingredients have been added to a pharmaceutical
composition such that the dissolution profile is extended over a longer
period of time than that of an immediate release formulation comprising a
similar pharmaceutical composition.

[0025] In some embodiments the at least one intermediate layer is a flat
layer separating at least two pharmaceutical layers. In some embodiments
the at least one intermediate layer has exposed edges. Exposed edges
allow for fluid to contact and dissolve the at least one intermediate
layer. In some embodiments the pharmaceutical formulations comprises a
coating covering the two or more pharmaceutical layers and the at least
one intermediate layer. The coating is configured to dissolve in vivo
more or less uniformly over the two or more pharmaceutical layers and the
at least one intermediate layer such that the at least one intermediate
layer is left exposed to the fluids that will dissolve the at least one
intermediate layer in vivo.

[0026] In some embodiments the at least one intermediate layer is or
comprises an impermeable membrane. In some embodiments the at least one
intermediate layer has a substantially higher dissolution rate than at
least one of the pharmaceutical layers. In some preferred embodiments the
at least one intermediate layer dissolves in a nearly immediate fashion
with respect to the dissolution of at least one of the pharmaceutical
layers. In some embodiments the at least one intermediate layer comprises
at least one of a monosaccharide or a disaccharide sugar, a starch (e.g.,
corn or potato starches), or any other suitable tablet ingredients known
in the art. In some preferred embodiments the at least one intermediate
layer comprises lactose. In some preferred embodiments, the intermediate
layer dissolves in a nearly immediate fashion as compared to the
dissolution rates of the respective pharmaceutical layers, e.g., such
that upon dissolution of the intermediate layer, substantially all of the
surface area of each of the two pharmaceutical layers is exposed. Thus,
in one embodiment, under a standard dissolution test the immediate
release layer is dissolved to the extent that at least two pharmaceutical
layers present in the pharmaceutical formulation are separated in less
than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 15, 20, 25 or 30 minutes.

[0027] Pharmaceutical formulations of drugs can be configured in various
ways and in a variety of dosage forms to modify a dissolution rate of the
drug. For example, one type of controlled-release pharmaceutical
formulation is a sustained-release pharmaceutical formulation.
Sustained-release pharmaceutical formulations can contain a variety of
excipients, such as retardant excipients (also referred to as release
modifiers) and/or fillers that are selected and incorporated into the
formulation in such a way as to slow the dissolution rate of the
formulation (and thereby slow the dissolution and/or release of the
zonisamide) under in vivo conditions as compared to an otherwise
comparable immediate-release formulation. Thus, a "comparable"
immediate-release formulation is one that is substantially identical to
the controlled-release formulation, except that that it is configured to
provide immediate-release instead of controlled-release under
substantially identical conditions.

[0028] The term "immediate-release" is used herein to specify a
formulation that is not configured to alter the dissolution profile of
the active ingredient (e.g., zonisamide, bupropion, naltrexone,
olanzapine, phentermine, topiramate, metformin, fluoxetine). For example,
an immediate-release pharmaceutical formulation may be a pharmaceutical
formulation that does not contain ingredients that have been included for
the purpose of altering the dissolution profile. An immediate-release
formulation thus includes drug formulations that take less than 30
minutes for substantially complete dissolution of the drug in a standard
dissolution test. A "standard dissolution test," as that term is used
herein, is a test conducted according to United States Pharmacopeia 24th
edition (2000) (USP 24), pp. 1941-1943, using Apparatus 2 described
therein at a spindle rotation speed of 100 rpm and a dissolution medium
of water, at 37° C., or other test conditions substantially
equivalent thereto. The term "controlled-release" is used herein in its
ordinary sense and thus includes pharmaceutical formulations that are
combined with ingredients to alter their dissolution profile. A
"sustained-release" formulation is a type of controlled-release
formulation, wherein ingredients have been added to a pharmaceutical
formulation such that the dissolution profile of the active ingredient is
extended over a longer period of time than that of an otherwise
comparable immediate-release formulation. A controlled-release
formulation thus includes drug formulations that take 30 minutes or
longer for substantially complete dissolution of the drug in a standard
dissolution test, conditions which are representative of the in vivo
release profile.

[0029] A pharmaceutical layer may be configured in various ways. For
example, in some embodiments a layer comprises a flat portion of a
pharmaceutical formulation. In some embodiments a layer comprises a
rounded portion of a pharmaceutical formulation. In some embodiments a
layer comprises a conical section of a pharmaceutical formulation. In
some embodiments a layer comprises an elliptical section of a
pharmaceutical formulation. In some embodiments a layer comprises a
sideways section of a pharmaceutical formulation. In some embodiments a
layer comprises a cubical section of a pharmaceutical formulation. In
some embodiments a layer comprises a wedge of a pharmaceutical
formulation. In some embodiments a layer comprises a substantial portion
of a pharmaceutical formulation. A substantial portion is preferably at
least about 25% of the pharmaceutical formulation and more preferably at
least about 50% of the pharmaceutical formulation.

[0030] In some embodiments at least one pharmaceutical layer reacts when
brought into contact with another of the pharmaceutical layers within the
layered pharmaceutical formulation. In some embodiments at least one
pharmaceutical layer does not react when brought into contact with
another of the pharmaceutical layers.

[0031] In some embodiments an intermediate layer is configured to dissolve
in vivo. Dissolving is the act of solvation wherein a solute is dissolved
in a solvent to create a solution. Dissolving in vivo means that the
dissolving takes place within an organism or within living tissue either
taken from or part of an organism. An organism is any living animal,
plant, bacteria or fungus. In preferred embodiments the organism is
human.

[0032] In some embodiments a dissolving intermediate layer separates at
least two of the pharmaceutical layers. In some embodiments the two
pharmaceutical layers contain different pharmaceutical compositions. In
some embodiments after the intermediate layer dissolves, the
pharmaceutical layers are no longer held together within the
pharmaceutical formulation. In some embodiments after the intermediate
layer dissolves, the pharmaceutical layers remain substantially intact. A
pharmaceutical layer remains substantially intact when it retains at
least about 50% of its original mass in a single entity post-dissolution
of the one or more intermediate layers. In preferred embodiments the
pharmaceutical layer remains substantially intact when it retains at
least about 75% of its original mass post-dissolution of the one or more
intermediate layers. In more preferred embodiments the pharmaceutical
layer remains substantially intact when it retains at least about 85% of
its original mass post-dissolution of the one or more intermediate
layers. In some embodiments each pharmaceutical layer has a different
dissolution rate. A dissolution rate is the solvation of a pharmaceutical
layer volume per unit time. In some embodiments one or more
pharmaceutical layers have similar dissolution rates. Preferably the one
or more intermediate layers have a higher dissolution rate than the two
or more pharmaceutical layers.

[0033] FIG. 1A illustrates a preferred embodiment of a pharmaceutical
formulation 100. The pharmaceutical formulation 100 comprises two
pharmaceutical layers 102A and 102B. Pharmaceutical layer 102A comprises
a pharmaceutical composition. In some embodiments of the pharmaceutical
formulation 100, the pharmaceutical layer 102B comprises the same
pharmaceutical composition as that of the pharmaceutical layer 102A. In
the illustrated embodiment of pharmaceutical formulation 100, the
pharmaceutical layer 102A comprises a different pharmaceutical
composition than that of the pharmaceutical layer 102B. The
pharmaceutical formulation 100 also comprises an intermediate layer 106.
In the illustrated embodiment the intermediate layer 106 is configured to
dissolve in vivo.

[0034] Each of the pharmaceutical layers 102A and 102B comprises one or
more pharmaceutical compositions. As illustrated in the pharmaceutical
formulation 100, the dosage amount of each pharmaceutical layer 102A and
102B is similar. The dosage strength of each pharmaceutical layer may
also be similar. In other embodiments the dosage amount and/or strength
of one pharmaceutical layer is much greater than that of another layer.
This difference in dosage amount or strength allows for individualized
treatment of symptoms that are addressed by increasing or decreasing a
dosage of one or more pharmaceutical layers while maintaining a dosage of
other layers. The amount or strength of dosage of a drug contained within
a pharmaceutical formulation will, of course, be dependent on the subject
being treated, on the subject's weight, the severity of the affliction,
the manner of administration and the judgment of the prescribing
physician.

[0035] The illustrated pharmaceutical formulation 100 includes, but is not
limited to, drugs for affecting weight loss, suppressing appetite and/or
treating an obesity-related condition in a patient. Specifically, the
illustrated pharmaceutical layer 102A comprises zonisamide and the
pharmaceutical layer 102B comprises bupropion. The intermediate layer 106
comprises lactose or a suitable monosaccharide sugar, disaccharide sugar
or a starch. In another embodiment, one or more of the pharmaceutical
layers comprises naltrexone, one or more of the pharmaceutical layers
comprises bupropion, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
naltrexone, one or more of the pharmaceutical layers comprises
zonisamide, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
naltrexone, one or more of the pharmaceutical layers comprises
fluoxetine, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises
olanzapine, one or more of the pharmaceutical layers comprises
zonisamide, and at least one intermediate layer comprises a
monosaccharide sugar, a disaccharide sugar or a starch. In another
embodiment, one or more of the pharmaceutical layers comprises metformin,
one or more of the pharmaceutical layers comprises zonisamide, and at
least one intermediate layer comprises a monosaccharide sugar, a
disaccharide sugar or a starch. In another embodiment, one or more of the
pharmaceutical layers comprises phentermine, one or more of the
pharmaceutical layers comprises topiramate, and at least one intermediate
layer comprises a monosaccharide sugar, a disaccharide sugar or a starch.

[0036] In some embodiments the presence of one drug in a pharmaceutical
formulation enhances the desired physiological effects and/or reduces
undesired physiological effects of one or more other drugs in the
pharmaceutical formulation. In some embodiments the presence of one or
more drugs in a pharmaceutical formulation enhances the desired
physiological effects of the drugs over the additive physiological
effects of the one or more drugs in comparable, but separate
pharmaceutical formulations when administered alone.

[0037] FIG. 1B illustrates the pharmaceutical formulation 100 of FIG. 1A
as a fluid, as represented by the arrow 108, begins to dissolve the
intermediate layer 106. In the illustrated embodiment, the fluid
comprises at least one bodily fluid selected from saliva, sweat, chyme,
mucus and bile. As the intermediate layer 106 dissolves the
pharmaceutical layers 102A and 102B begin to separate as shown. As noted
above, in some embodiments each pharmaceutical layer comprises the same
pharmaceutical composition. However, in the illustrated embodiment, the
pharmaceutical layers 102A and 102B each comprise a different
pharmaceutical composition. In some embodiments, one or more of the
pharmaceutical layers comprises a controlled-release formulation. In some
embodiments, one or more of the controlled-release formulations comprises
a sustained-release formulation.

[0039]FIG. 2A illustrates an embodiment of a second layered
pharmaceutical formulation 200. The second pharmaceutical formulation 200
comprises second pharmaceutical layers 202A, 202B and 202C. In some
embodiments two or more of the second pharmaceutical layers 202A, 202B
and 202C comprise the same pharmaceutical composition. In the illustrated
embodiment each of the pharmaceutical layers 202A, 202B and 202C
comprises a different pharmaceutical composition. The second
pharmaceutical formulation 200 also comprises an intermediate layer 106
configured to dissolve in vivo.

[0040]FIG. 2B illustrates the second layered pharmaceutical formulation
200 of FIG. 2A. The fluid, as represented by the arrow 108, has dissolved
an intermediate layer 106 and the second pharmaceutical layers 202A, 202B
and 202C are separated and left substantially intact.

[0041]FIG. 3 illustrates an embodiment of a third layered pharmaceutical
formulation 300. The third pharmaceutical formulation 300 comprises third
pharmaceutical layers 302A, 302B and 302C separated by an intermediate
layer 106. Each of the third pharmaceutical layers 302A, 302B and 302C
comprises one or more pharmaceutical compositions. As illustrated in the
third layered pharmaceutical formulation 300, the third pharmaceutical
layer 302A comprises a similar dosage volume to the third pharmaceutical
layer 302B. The third pharmaceutical layer 302C, however, comprises a
larger dosage volume than third pharmaceutical layers 302A or 302B. As
noted above with regard to FIG. 1, varying dosage amounts or strengths of
particular pharmaceutical layers within a pharmaceutical formulation
allows for individualized treatment of particular symptoms.

[0042] FIG. 4 illustrates an embodiment of a fourth layered pharmaceutical
formulation 400. The fourth pharmaceutical formulation 400 includes, but
is not limited to fourth pharmaceutical layers 402A and 402B and an
intermediate layer 106. The fourth pharmaceutical layer 402A comprises a
first drug 404A and a second drug 404B. The first drug 404A and the
second drug 404B are positioned within the fourth pharmaceutical layer
402A so as to be in physical contact with the other; no intermediate
layer 106 separates the first drug 404A from the second drug 404B within
the layer 402A. Similarly, the fourth pharmaceutical layer 402B comprises
a third drug 404C and a fourth drug 404D; no intermediate layer 106
separates the third drug 404C and the fourth drug 404D.

[0043] In the fourth pharmaceutical formulation 400 the intermediate layer
106 is disposed between fourth pharmaceutical layers 402C and 402B. In
this embodiment, the edges of intermediate layer 106 are not aligned with
the fourth pharmaceutical layers 402C and 402B. A space 408 allows for
fluids to interact with and dissolve the intermediate layer 106. Thus,
although the intermediate layer 106 is not flush with the outside edge of
the fourth pharmaceutical formulation 400, the intermediate layer 106 is
exposed for purposes of dissolution upon contact with bodily fluids.

[0044]FIG. 5 illustrates an embodiment of a fifth layered pharmaceutical
formulation 500 depicted after separation has occurred. The fifth
pharmaceutical formulation 500 includes, but is not limited to fifth
pharmaceutical layers 502A and 502B. The fifth pharmaceutical layers 502A
and 502B each include, but are not limited to one or more pharmaceutical
compositions.

[0045] The fifth pharmaceutical formulation 500 further comprises a first
intermediate layer 506A and a second intermediate layer 506B. In some
embodiments the first intermediate layer 506A is configured to physically
and chemically separate the fifth pharmaceutical layers 502A and 502B. In
some embodiments the second intermediate layer 506B is configured to
physically and chemically separate the fifth pharmaceutical layers 502A
and 502B. The first intermediate layer 506A and the second intermediate
layer 506B each comprise one or more formulations configured to dissolve
in vivo.

[0046]FIG. 6 illustrates an embodiment of a sixth layered pharmaceutical
formulation 600. The sixth pharmaceutical formulation 600 includes, but
is not limited to sixth pharmaceutical layers 602A and 602B and an
intermediate layer 106. The sixth pharmaceutical formulation 600 is
configured in a lenticular shape, wherein each pharmaceutical layer 602A
and 602B comprises a single convex shape.

[0047] Pharmaceutical layers may be configured in various shapes. For
example, pharmaceutical layers may be configured in elliptical shapes,
spherical shapes, oblong shapes, square shapes or flat shapes. In some
embodiments pharmaceutical formulations are combined with fillers or
excipients and placed in tablets, granules or capsules for later
administration. In some embodiments the tablets are configured in
spherical, elliptical, lenticular or capsule shapes.

[0048]FIG. 7 illustrates another embodiment of a seventh layered
pharmaceutical formulation 700. The seventh pharmaceutical formulation
700 includes, but is not limited to seventh pharmaceutical layers 702A,
702B, 702C, 702D, 702E and 702F. Each seventh pharmaceutical layer 702A,
702B, 702C, 702D, 702E and 702F comprises one or more pharmaceutical
compositions. Each seventh pharmaceutical layer 702A, 702B, 702C, 702D,
702E and 702F is in a wedge shape. The seventh pharmaceutical formulation
700 additionally comprises an intermediate layer 106 disposed between
seventh pharmaceutical layers 702B, 702C and 702D and also between
seventh pharmaceutical layers 702A, 702F and 702E. As described above the
intermediate layer 106 is configured to dissolve in vivo upon contact
with a certain type of bodily fluid. The seventh pharmaceutical
formulation 700 additionally comprises a special intermediate layer 706
disposed between seventh pharmaceutical layers 702A and 702B and between
seventh pharmaceutical layers 702D and 702E. The special intermediate
layer 706 is configured to dissolve under bodily conditions different
than those conditions that dissolve intermediate layer 106. Upon
dissolution of the special intermediate layer 706, the seventh
pharmaceutical layers 702A and 702B and the seventh pharmaceutical layers
702D and 702E are left substantially intact.

[0049] For example, if intermediate layer 106 were configured to dissolve
under the acidic conditions of the stomach in a human patient, special
intermediate layer 706 may be configured to dissolve only after the
pharmaceutical formulation 700 reaches the duodenum. In some embodiments
at least one of the pharmaceutical layers comprises an enteric coating.

Manufacture of Pharmaceutical Formulations

[0050] As noted above, pharmaceutical formulations may be configured in
various shapes and sizes for ease of administration to a patient.
Manufacture of pharmaceutical formulations configured in tablets
comprises steps known in the art. For example, tablets may be prepared
through wet-granulation, dry-granulation or direct compression. Layered
pharmaceutical formulations may be configured in tablet form in a similar
manner. To manufacture each pharmaceutical layer, one or more drugs are
obtained in, for example, a crystalline, amorphous or powdered form, and
mixed with or without diluents and/or excipients into a solid with
pressure. The solid pharmaceutical layer is added with other
pharmaceutical layers and/or intermediate layers and configured in a
desired tablet geometry with pressure.

[0052] In some embodiments pharmaceutical formulations include, but are
not limited to controlled-release formulations. In some embodiments the
controlled-release formulations include, but are not limited to
sustained-release formulations.

Pharmaceutical Formulations to Treat Obesity

[0053] In some embodiments the layered pharmaceutical formulation may be
used to treat obesity. Obesity is a disorder characterized by the
accumulation of excess fat in the body. Obesity has been recognized as
one of the leading causes of disease and is emerging as a global problem.
Increased instances of complications from obesity, such as hypertension,
non-insulin-dependent diabetes mellitus, arteriosclerosis, dyslipidemia,
certain forms of cancer, sleep apnea and osteoarthritis, have been
related to increased instances of obesity in the general population.

[0054] Prior to 1994, obesity was generally considered a psychological
problem. The discovery of the adipostatic hormone leptin in 1994 brought
forth the realization that in certain cases, obesity may have a
biochemical basis. The corollary to this realization was the idea that
treatment of obesity may be achieved by chemical approaches. Since then,
a number of such chemical treatments have entered the market.

[0055] Various methods of affecting weight loss, suppressing appetite
and/or treating an obesity-related condition in a patient involve
administering certain drugs or combinations thereof. For example, a
number of references disclose the administration of certain weight loss
formulations that include an anticonvulsant, an opioid antagonist and/or
a norepinephrine reuptake inhibitor (NRI) to a patient in need thereof to
affect weight loss. See, for example, U.S. Patent Application Publication
Nos. 2004/0033965; 2004/0198668; 2004/0254208; 2005/0137144;
2005/0143322; 2005/0181070; 2005/0215552; 2005/0277579; 2006/0009514;
2006/0142290; 2006/0160750 and 2006/0079501, all of which are hereby
incorporated by reference in their entireties. Weight gain has been a
major concern with certain of the newer antidepressants, particularly,
with paroxetine (PAXIL® PAXIL CR®) and mirtazapine (Fava, J.
Clin. Psych. 61 (suppl. 11):37-41 (2000); Carpenter et al, J. Clin.
Psych. 60:45-49 (1999); Aronne et al, J. Clin. Psych. 64 (suppl. 8):22-29
(2003), both of which are incorporated by reference herein in their
entirety).

[0056] Other descriptions of bupropion, zonisamide, controlled-release
zonisamide and combinations thereof are disclosed in U.S. Provisional
Patent Application Nos. 60/740,034, filed on Nov. 28, 2005; 60/832,110,
filed on Jul. 19, 2006; 60/835,564, filed on Aug. 4, 2006; and U.S.
patent application Ser. No. 11/194,201 entitled COMBINATION OF BUPROPION
AND A SECOND COMPOUND FOR AFFECTING WEIGHT LOSS, filed on Aug. 1, 2005;
all of which are hereby incorporated by reference in their entireties.

[0057] For methods of administering pharmaceutical compositions useful for
affecting weight loss, suppressing appetite and/or treating
obesity-related conditions in individuals controlled-release formulations
help to suppress some if not all of the negative side effects that may
arise from administration of such medication. Even in controlled-release
formulations, however, the administration of certain anticonvulsants or
opioid receptor antagonists at a full dosage may initially incur severe
adverse side effects. Thus, at least initially, patients may be unable to
tolerate a full dosage of the prescribed drug, which may include, but is
not limited to an anticonvulsant or an opioid receptor antagonist. This
intolerance may lead to more severe side effects and/or premature
abandonment of the medication and/or the treatment program.

[0058] Administering combinations of drugs, for example, a combination
including, but not limited to an anticonvulsant or an opioid receptor
antagonist in combination with an antidepressant may enhance the ability
of the anticonvulsant to affect weight loss, but does not necessarily
eliminate the initial adverse side effects that may accompany the
administration of the anticonvulsant or the opioid receptor antagonist.
In some embodiments a system comprises a layered pharmaceutical for
minimizing side effects during treatment of obesity. In some embodiments
a method comprises administering a layered pharmaceutical formulation
comprising an anticonvulsant or the opioid receptor antagonist to affect
weight loss while minimizing or eliminating the initial adverse side
effects on the patient.

[0059] Thus, some preferred embodiments, the layered pharmaceutical
formulation is useful for the treatment of obesity and/or for affecting
weight loss. Some preferred embodiments comprise at least one of an
antidepressant and an anticonvulsant. Other preferred embodiments
comprise at least one of an antidepressant and an opioid receptor
antagonist. Other preferred embodiments comprise at least one of an
anticonvulsant and an opioid receptor antagonist. Other preferred
embodiments comprise at least one of an anticonvulsant and an
antidiabetic.

Antidepressants and Psychotherapeutics

[0060] In some embodiments an antidepressant comprises a dopamine reuptake
inhibitor or receptor antagonist. Examples of dopamine reuptake
inhibitors include, but are not limited to phentermine and
pharmaceutically acceptable salts or prodrugs thereof. Examples of
dopamine receptor antagonists include, but are not limited to
haloperidol, ocaperidone, risperidone, olanzapine, quetiapine,
amisulpride, and pimozide and pharmaceutically acceptable salts or
prodrugs thereof. In some embodiments the antidepressant comprises a
norepinephrine reuptake inhibitor. Examples of norepinephrine reuptake
inhibitors include, but are not limited to bupropion, thionisoxetine,
atomoxetine and reboxetine and pharmaceutically acceptable salts or
prodrugs thereof. Other embodiments include, but are not limited to those
in which the antidepressant is a dopamine agonist. Dopamine agonists
available on the market include cabergoline, amantadine, lisuride,
pergolide, ropinirole, pramipexole, and bromocriptine. In some
embodiments the antidepressant comprises a serotonin reuptake inhibitor.
Examples of serotonin reuptake inhibitors include, but are not limited to
fluoxetine and pharmaceutically acceptable salts or prodrugs thereof.

[0061] Throughout the disclosure of the present specification the term
"pharmaceutically acceptable salt" refers to a formulation of a compound
that does not cause significant irritation to an organism to which it is
administered and does not abrogate the biological activity and properties
of the compound. Pharmaceutical salts can be obtained by reacting a
compound of the disclosure with inorganic acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid and the like. Pharmaceutical salts can also be obtained by
reacting a compound of the disclosure with a base to form a salt such as
ammonium salt, an alkali metal salt such as a sodium or a potassium salt,
an alkaline earth metal salt such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl) methylamine and salts thereof with amino acids such
as arginine, lysine and the like.

[0062] The term "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they are easier to administer than the parent drug. They can,
for instance, be bioavailable by oral administration whereas the parent
is not. The prodrug can also have improved solubility in pharmaceutical
compositions over the parent drug or can demonstrate increased
palpability or be easier to formulate.

[0063] An example, without limitation, of a prodrug would be a compound of
the present disclosure which is administered as an ester (the "prodrug")
to facilitate transmittal across a cell membrane where water solubility
is detrimental to mobility but which then is metabolically hydrolyzed to
the carboxylic acid, the active entity, once inside the cell where
water-solubility is beneficial. A further example of a prodrug might be a
short peptide (polyaminoacid) bonded to an acid group where the peptide
is metabolized to provide the active moiety.

[0064] Bupropion, whose chemical name is
(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is
the active ingredient in the drugs marketed as ZYBAN® and
WELLBUTRIN®, and is usually administered as a hydrochloride salt.
Throughout the present disclosure, whenever the term "bupropion" is used,
it is understood that the term encompasses bupropion as a free base, or
as a physiologically acceptable salt thereof, or as a bupropion
metabolite or salt thereof.

[0065] The metabolites of bupropion suitable for inclusion in the methods
and compositions described herein include the erythro- and threo-amino
alcohols of bupropion, the erythro-amino diol of bupropion, and
morpholinol metabolites of bupropion. In some embodiments, the metabolite
of bupropion is
(±)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol. In
some embodiments the metabolite is
(-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, while in
other embodiments, the metabolite is (+)-(2S,3
S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol. Preferably, the
metabolite of bupropion is
(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, which is
known by its common name of radafaxine. The scope of the present
disclosure includes the above-mentioned metabolites of bupropion as a
free base or as a physiologically acceptable salt thereof.
Controlled-release bupropion formulations of bupropion are known in the
art. For example, U.S. Pat. No. 6,905,708 discloses a once-daily dosage
configured to deliver bupropion in vivo over a 6 to 12 hour period.

[0066] Olanzapine, whose chemical name is
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,
is used as a psychotherapeutic agent primarily for the treatment of
schizophrenia, acute manic episodes in bipolar disorder acute,
maintenance treatment in bipolar disorder and agitation associated with
both these disorders. Throughout the present disclosure, whenever the
term "olanzapine" is used, it is understood that the term encompasses
olanzapine as a free base, or as a physiologically acceptable salt
thereof, or as a olanzapine metabolite or salt thereof.

[0067] Olanzapine displays linear kinetics. Its elimination half-life
ranges from 21 to 54 hours. Steady state plasma concentrations are
achieved in about a week. Olanzapine undergoes extensive first pass
metabolism and bioavailability is not affected by food.

[0068] The psychotherapeutic agent may be selected from the group
consisting of mirtazapine, setiptiline, paroxetine, venlafaxine,
olanzapine, bupropion, risperidone, lamotrogine, risperidone, a lithium
salt, valproic acid, and pharmaceutically acceptable salts or prodrugs
thereof. In some embodiments the psychotherapeutic agent is an
antidepressant, an antimigrane, an antibipolar, an antimania drug, a mood
stabilizer, or an antiepileptic. Examples of antidepressants include
paroxetine, mirtazapine, and bupropion. Examples of antibipolar drugs
include lithium, valproate, carbamezepine, oxycarbamezepine, lamotrogine,
tiagabine, olanzapine, clozapine, risperidone, quetiapine, aripiprazole,
ziprasidone, and benzodiazepines. Also included are pharmaceutically
acceptable salts or prodrugs of these drugs, extended release or
controlled release formulations of the above drugs, as well as
combinations of the above drugs.

[0069] Fluoxetine is a selective serotonin reuptake inhibitor (SSRI),
whose chemical name is
N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine, is used
primarily for the treatment of depression (including pediatric
depression), obsessive-compulsive disorder (in both adult and pediatric
populations), bulimia nervosa, panic disorder, premenstrual dysphoric
disorder, hypochondriasis and body dysmorphic disorder. Throughout the
present disclosure, whenever the term "fluoxetine" is used, it is
understood that the term encompasses fluoxetine as a free base, or as a
physiologically acceptable salt thereof, or as a fluoxetine metabolite or
salt thereof.

[0070] Fluoxetine has a bioavailability of approximately 72%, and peak
plasma concentrations are reached in 6 to 8 hours. It is highly bound to
plasma proteins, mostly albumin. Its elimination half-life ranges from 1
to 3 days--after a single dose--to 4 to 6 days (after long-term use) in
healthy adults, and is prolonged in those with liver disease. The
half-life of norfluoxetine is longer (16 days after long-term use).
Complete excretion of the drug may take several weeks.

[0071] The SSRI can be selected from fluoxetine, fluvoxamine, sertraline,
paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and
venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.
In some embodiments, the SSRI is fluoxetine or a pharmaceutically
acceptable salt or prodrug thereof.

[0072] Fluoxetine has a physiological half life of about 24 hours, whereas
that of naltrexone is about 1.5 hours. However their metabolites may
demonstrate half-lives in excess of 24 hours. Thus, in some cases, it may
be beneficial to administer one dose of fluoxetine per day in conjunction
with two or three or more doses of naltrexone throughout the day.
Naltrexone may also be in a time-release formulation where the dose is
administered once a day, but naltrexone gradually enters the blood stream
throughout the day, or in the course of a 12 hour period.

[0073] Symptoms of the obsessive compulsive disorders are inhibited in
individuals being administered fluoxetine and naltrexone. Adverse events
associated with the obsessive compulsive disorders are reduced in
individuals being administered fluoxetine and naltrexone. The effects of
administration of both fluoxetine and naltrexone on obsessive compulsive
disorder are synergistic compared to effects of those expected by
administration of fluoxetine and naltrexone alone.

[0075] Phentermine is an example of a dopamine reuptake inhibitor with a
chemical name 2-methyl- 1 -phenylpropan-2-amine and 2-methyl-amphetamine.
Throughout the present disclosure, whenever the term "phentermine" is
used, it is understood that the term encompasses phentermine as a free
base, or as a physiologically acceptable salt thereof, or as a
phentermine metabolite or salt thereof.

Antidiabetic

[0076] In some embodiments an antidiabetic includes, but is not limited to
a biguanide, glucosidase inhibitor, insulin, meglitinide, sulfonylurea or
a thiazolidinedione. In some embodiments a biguanide comprises metformin
hydrochloride. In some embodiments a glucosidase inhibitor includes, but
is not limited to acarbose and miglitol. Examples of insulin include, but
are not limited to human insulin, pork insulin, beef insulin, beef-pork
insulin, insulin from different sources such as recombinant DNA and
animal sources, as well as regular, NPH, and LENTE® types of insulin.
Other examples of insulin include, but are not limited to mixtures of the
various forms of insulin (e.g. NPH and regular human and pork insulin).
Other examples of insulin include mixtures of Insulin Lispro Protamine
and Insulin Injection (rDNA origin), a 50/50 (or a 70/30) mixture of
Human Insulin Isophane Suspension and Human Insulin Injection, a 70/30
mixture of NPH Human Insulin Isophane Suspension and Human Insulin
Injection (rDNA), insulin glargine, insulin lispro, insulin aspart, as
well as insulin mixed with other ingredients such as zinc crystals or in
a phosphate buffer. Insulin may be from Saccharomyces cerevisiae or other
sources. Examples of meglitinides include, but are not limited to
nateglinide and repaglinide. Examples of sulfonylureas include, but are
not limited to glimepiride, glyburide, glibenclamide, gliquidone,
gliclazide, chlorpropamide, tolbutamide, tolazamide and glipizide.
Examples of thiazolidinediones include, but are not limited to
rosiglitazone and pioglitazone. Also included are extended release
formulations of the above drugs, as well as combinations of the above
drugs and pharmaceutically acceptable salts or prodrugs thereof.

[0077] As mentioned above, in certain embodiments, the antidiabetic is
metformin. Metformin, whose chemical name is
1-(diaminomethylidene)-3,3-dimethyl-guanidine, is often used in the
treatment of diabetes mellitus type 2, especially when accompanied
obesity and insulin resistance. Metformin has also been proven to reduce
the cardiovascular complications of diabetes.

Anticonvulsants

[0078] In some embodiments, the anticonvulsant is selected from the group
including, but not limited to zonisamide, topiramate, nembutal,
lorazepam, clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin,
phenytoin, carbamazepine, balproate, felbamate, lebetiracetam,
oxcarbazepine, lamotrigine, methsuximide and ethosuxmide.

[0079] Zonisamide is a marketed anticonvulsant indicated as adjunctive
therapy for adults with partial onset seizures. Without being bound by
any particular theory, it is believed that the mechanism of antiepileptic
activity appears to be: (1) sodium-channel blocking; and (2) reduction of
inward T-type calcium occurrence. In addition, zonisamide binds to the
GABA/benzodiazepine receptor complex without producing change in chloride
flux. Further, zonisamide facilitates serotonergic and dopaminergic
neurotransmission and possesses a weak inhibitory effect on carbonic
anhydrase.

[0080] Zonisamide has been shown to cause significant weight loss
(comparable to marketed weight loss medications) in patients presenting
primary obesity. It has been postulated that the affect of zonisamide on
the CNS concentration of serotonin, dopamine and carbonic anhydrase is
responsible for this effect. There is evidence that zonisamide increases
serotonin and dopamine synthesis rates herein. There is further evidence
suggesting that zonisamide stimulates dopamine D2 receptors.

[0081] Zonisamide can be formulated in a controlled- or sustained-release
tablet or gel form. This allows a patient newly prescribed zonisamide to
ramp up the dosage level over a period of several days. This increase in
dosage form allows the patient to avoid some of the negative side effects
that have been exhibited during the initial administration of zonisamide
to a patient. Some of these initial side effects include a shock to the
body. Although patients who start with a full dose of zonisamide will
become acclimated to the dosage over a period of time, the negative side
effects accompanying the initial shock to the body can be avoided with a
method wherein dosages are increased over a period of several days.

[0082] In a pharmaceutical composition with a drug such as bupropion, a
method of administering sustained-release zonisamide in a layered tablet
can reduce shock to the body while maximizing bioavailability, and thus
have a maximum effect for prevention of weight gain and/or treatment of
obesity.

[0083] Although the exact dosages will be determined on a drug-by-drug
basis, in most cases some generalizations regarding the dosage can be
made. Some descriptions of appropriate unit dosages of drugs including,
but not limited to bupropion, zonisamide, controlled-release zonisamide
and combinations thereof are disclosed in U.S. Provisional Patent
Application No. 60/740034 entitled CONTROLLED RELEASE FORMULATION OF
ZONISIMIDE, filed on Nov. 28, 2005; and U.S. patent application Ser. No.
11/194202 entitled COMBINATION OF BUPROPION AND A SECOND COMPOUND FOR
AFFECTING WEIGHT LOSS, filed on Aug. 1, 2005; which are hereby
incorporated by reference in their entireties, and U.S. Patent
Publication Nos. 2005/0215552 and 2006/0079501 mentioned previously.

[0084] In some embodiments the anticonvulsant is a γ-amino butyric
acid (GABA) inhibitor, a GABA receptor antagonist or a GABA channel
modulator. By "GABA inhibitor" it is meant a compound that reduces the
production of GABA in the cells, reduces the release of GABA from the
cells, or reduces the activity of GABA on its receptors, either by
preventing the binding of GABA to GABA receptors or by minimizing the
effect of such binding. The GABA inhibitor may be a 5-HT1b agonist or
another agent that inhibits the activity of NPY/AgRP/GABA neurons. In
addition, the GABA inhibitor may suppress the expression of the AgRP
gene, or the GABA inhibitor may suppress the production or release of
AgRP. It is, however, understood that a 5-HT1b agonist may inhibit the
NPY/AgRP/GABA neuron (and therefore activate pro-opiomelanocortin (POMC)
neurons) without acting as an inhibitor of the GABA pathway.

[0085] In certain other embodiments the GABA inhibitor increases the
expression of the POMC gene. In some of these embodiments, the GABA
inhibitor increases the production or release of POMC protein. In certain
other of these embodiments, the GABA inhibitor increases the activity on
POMC expressing neurons.

[0086] In some embodiments, the GABA inhibitor is topiramate. Topiramate,
whose chemical name is
2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate, is
often used to treat epilepsy, Lennox-Gastaut syndrome (a disorder causing
seizures and developmental delays), neuropathic pain, bipolar disorder,
obesity including reduction of binge eating, alcoholism, Post Traumatic
Stress Disorder, infantile spasm, bulimia nervosa, or
obsessive-compulsive disorder or to assist smoking cessation or prevent
migraines. Generally, initial doses of topiramate are low and increased
in slow steps. The usual initial dose is 25 to 50 mg daily in 2 single
doses. Recommended increments vary, but are usually between 25 mg and 50
mg every 1 or 2 weeks. Common doses for maintenance treatment include,
but are not limited to doses of approximately 100 to 200 mg daily.

Opioid Receptor Antagonists

[0087] In certain embodiments the opioid antagonist antagonizes a
μ-opioid receptor (MOP-R) in a mammal. The mammal may be selected from
the group including, but not limited to mice, rats, rabbits, guinea pigs,
dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees,
and apes, and humans.

[0088] In some embodiments the opioid antagonist is selected from the
group including, but not limited to alvimopan, norbinaltorphimine,
nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine, and
pharmaceutically acceptable salts or prodrugs thereof

[0089] In other embodiments, the opioid antagonist is a partial opioid
agonist. Compounds of this class have some agonist activity at opioid
receptors. However, because they are weak agonists, they function as
de-facto antagonists. Examples of partial opioid agonists include, but
are not limited to pentacozine, buprenorphine, nalorphine, propiram, and
lofexidine.

[0091] It is marketed as its hydrochloride salt, naltrexone hydrochloride,
under the trade name REVIA®. REVIA® is an immediate release
formulation of naltrexone, with 100 mg strength. The maximum serum
concentration of immediate release naltrexone is reached very rapidly,
typically a Tmax of approximately 1 hour. Immediate release
naltrexone can induce side effects such as nausea, which is attributable
to the maximum blood plasma concentration levels (Cmax).

[0092] An oral dosage form of naltrexone that is able to effect naltrexone
release at a rate sufficiently slow to ameliorate side effects, yet
sufficiently fast to achieve good bioavailability would provide a
significant improvement in dosing compliance and convenience. Likewise,
an improved dosage form which lowered the incidence of gastrointestinal
side-effects would also be of significant value.

[0093] In some embodiments, oral dosage forms of naltrexone are effective
to provide an AUC between about 75% to about 125% of 50 mg immediate
release naltrexone tablets. In some embodiments oral dosage forms of
naltrexone provide an amount of a retardant excipient that is effective
to provide a Cmax that is less than or equal to about 80% of the
Cmax of 50 mg immediate release naltrexone tablets.

[0094] Formulations of controlled- or sustained-release naltrexone have
been disclosed in U.S. Provisional Patent Application Ser. No.
60/811,251, filed Jun. 5, 2006, which is hereby incorporated by reference
in its entirety. In some embodiments, oral dosage forms of naltrexone are
effective to provide an AUC between about 75% to about 125% of 50 mg
immediate release naltrexone tablets. In some embodiments oral dosage
forms of naltrexone comprise an amount of a retardant excipient that is
effective to provide a Cmax that is less than or equal to about 80%
of the Cmax of 50 mg immediate release naltrexone tablets.

[0095] Those skilled in the art informed by the guidance provided herein
can formulate oral dosage forms described herein. For example, one
skilled in the art could formulate an oral dosage form that includes, but
is not limited to an amount of naltrexone effective to provide an AUC
between about 75% to about 125% of 50 mg immediate release naltrexone
tablets, and an amount of an appropriate retardant excipient effective to
provide a Cmax that is less than or equal to about 80% of the
Cmax of 50 mg immediate release naltrexone tablets. Further, given
the guidance provided herein, the skilled artisan could formulate an oral
dosage form having a pharmacodynamic profile characterized by coverage of
greater than or equal to 80% of the opioid receptors in the hypothalamus.

Examples

[0096] Below are found specific examples of pharmaceutical compositions
that may be formed into layered pharmaceutical formulations of the
present disclosure.

[0097] Thus, as illustrated in Tables 1-3 above, embodiments of
pharmaceutical formulations may comprise controlled-release (e.g.,
sustained release in the illustrated embodiments) formulations of
bupropion, zonisamide and/or naltrexone. In one embodiment, a layered
pharmaceutical formulation is a tablet comprising a first layer
comprising a controlled-release zonisamide and a second layer comprising
a bupropion. In another embodiment a layered pharmaceutical formulation
is a tablet comprising a first layer comprising a controlled-release
naltrexone and a second layer comprising a controlled-release bupropion.
In some embodiments the first layer and the second layer are separated by
an intermediate layer comprising lactose or other suitable
fast-dissolving ingredient.

[0098] The oral dosage forms of pharmaceutical formulations can, if
desired, be presented in a unit dosage package which may contain one or
more unit dosage forms containing the active ingredient. The unit dosage
package may for example comprise metal or plastic foil, such as a blister
pack. The unit dosage package may be accompanied by instructions for
administration. The unit dosage package may also be accompanied with a
notice associated with the container in form prescribed by a governmental
agency regulating the manufacture, use, or sale of pharmaceuticals, which
notice is reflective of approval by the agency of the form of the drug
for human or veterinary administration. Such notice, for example, may be
the labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. Compositions
comprising a compound of the disclosure formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an appropriate
container, and labeled for treatment of an indicated condition.

[0099] Novel methods and systems for administering weight loss medications
are described in co-pending application entitled METHODS FOR
ADMINISTERING WEIGHT LOSS MEDICATIONS filed on the same day as the
present application, which is hereby incorporated by reference in its
entirety.

[0101] In one embodiment a layered pharmaceutical formulation for the
administration of two or more active pharmaceutical ingredients comprises
a first pharmaceutical layer comprising a first active pharmaceutical
ingredient, a second pharmaceutical layer comprising a second active
pharmaceutical ingredient and at least one intermediate layer disposed
between the first and the second pharmaceutical layers, wherein the at
least one intermediate layer is configured to dissolve in vivo to thereby
leave the first and the second pharmaceutical layers substantially
intact.

[0102] In some embodiments each of the first and the second pharmaceutical
layers comprises a dissolution profile substantially similar to a
singularly compressed tablet of a similar composition. In some
embodiments each of the first and the second pharmaceutical layers
comprises a different pharmaceutical composition. In some embodiments at
least one of the first and the second pharmaceutical layers comprises a
controlled-release pharmaceutical composition. In some embodiments the
controlled-release pharmaceutical composition comprises a sustained
release pharmaceutical composition.

[0103] In some embodiments at least one of the first and the second
pharmaceutical layers comprises zonisamide. In some embodiments the
zonisamide comprises a controlled-release zonisamide. In some embodiments
the controlled-release zonisamide comprises a sustained-release
zonisamide. In some embodiments at least one of the first and the second
pharmaceutical layers comprises bupropion. In some embodiments the
bupropion comprises a controlled-release bupropion. In some embodiments
the controlled-release bupropion comprises a sustained-release bupropion.
In some embodiments at least one of the first and the second
pharmaceutical layers comprises naltrexone. In some embodiments at least
one of the first and the second pharmaceutical layers comprises
fluoxetine.

[0104] In some embodiments at least one of the first and the second
pharmaceutical layers comprises olanzapine. In some embodiments at least
one of the first and the second pharmaceutical layers comprises an
antidiabetic. In some embodiments the antidiabetic comprises metformin.
In some embodiments at least one of the first and the second
pharmaceutical layers comprises topiramate. In some embodiments at least
one of the first and the second pharmaceutical layers comprises
phentermine. In some embodiments the at least one intermediate layer
comprises at least one of a monosaccharide sugar, a disaccharide sugar,
or a starch. In some embodiments the at least one intermediate layer
comprises lactose.

[0105] In one embodiment a method for affecting weight loss, suppressing
appetite and/or treating an obesity-related condition in a patient
comprises providing a first dosage of the layered pharmaceutical
formulation to a patient in need thereof on a first day and providing a
second dosage of the layered pharmaceutical formulation to the patient on
a second day. In some embodiments the first dosage is greater than the
second dosage. In some embodiments the second dosage is greater than the
first dosage.

[0106] In one embodiment a method for treating an obesity related
condition in a patient comprises identifying a patient with an obesity
related condition or at risk of an obesity related condition comprises
providing a first dosage of the layered pharmaceutical formulation of
claims 1 to the patient on a first day and providing a second dosage of
the layered pharmaceutical formulation to the patient on a second day. In
some embodiments the first dosage is different than the second dosage. In
some embodiments the second dosage is greater than the first dosage.

[0107] In one embodiment use of a first compound and a second compound in
the formulation of a medicament for affecting weight loss, suppressing
appetite or treating an obesity-related condition, wherein the medicament
comprises a layered pharmaceutical formulation of the present invention.

[0108] It will be appreciated by those skilled in the art that various
modifications and changes can be made without departing from the scope of
the disclosure. Such modifications and changes are intended to fall
within the scope of the disclosure, as defined by the appended claims.

Patent applications by Anthony Mckinney, San Diego, CA US

Patent applications by Eckard Weber, San Diego, CA US

Patent applications by Gary Tollefson, Indianapolis, IN US

Patent applications by Rick Soltero, Holly Springs, NC US

Patent applications by OREXIGEN THERAPEUTICS, INC.

Patent applications in class PREPARATIONS CHARACTERIZED BY SPECIAL PHYSICAL FORM

Patent applications in all subclasses PREPARATIONS CHARACTERIZED BY SPECIAL PHYSICAL FORM